Preeclampsia is a syndrome of hypertension, edema, and proteinuria. It affects about 5-10% of pregnant women, and results in substantial maternal and fetal morbidity and mortality. Symptoms of preeclampsia typically appear after the 20th week of pregnancy and are usually detected by routine screening of the pregnant woman's blood pressure and urine. Such routine screening methods, however, are ineffective for early diagnosis.
FMS-like tyrosine kinase-1 (Flt-1) is a membrane-spanning tyrosine kinase receptor that is differentially expressed in endothelial cells. It is highly expressed by trophoblast cells, which contribute to the formation of the placenta during pregnancy. Vascular endothelial growth factor (VEGF), which is an endothelial cell-specific mitogen, an angiogenic inducer, and a mediator of vascular permeability, binds as a homodimer to Flt-1. Placental growth factor (PlGF) is a member of the VEGF family that also is involved in development of the placenta. PlGF is expressed by cytotrophoblasts and syncytiotrophoblasts, can induce proliferation, migration, and activation of endothelial cells, and binds as a homodimer to Flt-1. Thus, VEGF and PlGF both contribute to mitogenic activity and angiogenesis during development of the placenta.
sFlt-1 is a soluble form of the Flt-1 receptor, and, thus, is also referred to as soluble VEGF receptor-1. It is a splice variant of the Flt-1 receptor that lacks the transmembrane and cytoplasmic domains of the Flt-1 receptor but contains seven IgG-like domains of the external portion of the receptor Like the Flt-1 receptor, sFlt-1 binds to VEGF and PlGF; however, it does not stimulate mitogenesis of endothelial cells. Rather, sFlt-1 prevents proteins from initiating blood vessel growth. It has been identified as a biomarker for the diagnosis of preeclampsia (see, e.g., McKeeman et al., Amer. J. of Obstetrics and Gynecology 191: 1240-1246 (2004)).
Immunoassays, such as enzyme-linked immunosorbent assays (ELISAs), have been developed to measure free and sFlt-1 complexed with VEGF in fluid samples (see, e.g., Karumanchi et al., U.S. Pat. No. 7,335,362, which issued Feb. 26, 2008, and Belgore et al., Clin. Sci. 100: 567-575 (2001)). There remains a need, however, for new materials, methods, and kits for determining the concentration of sFlt-1 in a test sample, such as in the diagnosis of preeclampsia and cardiovascular disease. There also is a need for new compositions and methods for treatment of a patient in therapeutic or prophylactic need of an antagonist of sFlt-1, such as a patient at risk for or having preeclampsia or a cardiovascular disease. The present disclosure seeks to address such needs. These and other objects and advantages of the present disclosure will become apparent from the detailed description provided herein.